Major sequela from the surgical management of prostate cancer is post-operative erectile dysfunction (ED). Advances in the field of neurourology have focused on the development and implementation of strategies for preserving the neurogenic basis of penile erection and functional integrity of the cavernous nerves (CN) following RP and thus maximizing postoperative erectile function outcomes. Following injury to the autonomic CN, there is a microenvironment change that predisposes the axons to degeneration with a proportion of nerve fibers which will regenerate with neurotrophic stimulus. The cellular and molecular mechanisms promoting neuropathy following CN injury is only recently been investigated with strong support for the involvement of cytokine induction and inflammatory mechanisms which lead to axonal degeneration. Now, the major challenge is identifying the key molecular events and signal transduction networks which lead to CN degeneration after injury or even in disease states such as diabetes mellitus and aging. This work is of particular importance because identification of key molecular switches that lead to CN dysfunction may lead to new treatment paradigms for this important problem in sexual medicine. In this application, we propose to address these issues by studying how the cytokine (TNF-?) and inflammatory (macrophage) milieu serve as a critical upstream activator of RhoA/Rho-kinase (ROCK) signaling in the major pelvic ganglion (MPG) after CN injury. Activation of ROCK signaling in the MPG promotes neuronal cell body apoptosis and thus reduction of synaptic transmission through the CN to the end-organ penis. Using a combination of in vitro myograph experiments, ex vivo explanted MPG measurements of neuritogenesis, and in vivo erectile physiology hemodynamic changes in an animal model of CN injury, we are poised to extend our work on RhoA/ROCK signaling in the MPG which was funded by a previous NIDDK K08 award application. As cytokines, macrophage chemoattraction, and ROCK signaling is easily manipulated by pharmacologic inhibitors, this work will not only add to our basic understanding of CN pathophysiology after injury, but also provide potential new therapeutic options for neurogenic-ED.